The clinical pharmacology of antineoplastic agents used in the treatment of pediatric malignancies is studied. Emphasis is placed on the role of clinical pharmacologic monitoring and on both pre-clinical and clinical pharmacologic studies of Phase I agents. The clinical pharmacology of orally administered antileukemic agents have been evaluated and the limited bioavailability and variable drug levels of 6-MP achieved following oral administration has been documented. Studies are underway to determine the extent to which this phenomenon is the cause of treatment failure. The interaction of 6-MP and allopurinol, a unique example of hepatic first-pass metabolism in cancer chemotherapy has been examined in both subhuman primates and in man. Additional efforts to optimize 6-MP administration have based on in vitro studies which have demonstrated a need for prolonged exposure to cytocidal concentrations of drug to maximize leukemic cell kill. A clinical protocol evaluating prolonged intravenous 6-MP infusions in a Phase I setting is underway. Pre-clinical and clinical pharmacokinetic studies of the new agent, Tiazofurin, have been pursued and a pediatric Phase I study of this agent is in progress. A major effort of this project is to study experimental approaches to the treatment of both meningeal and non-meningeal CNS malignancy. A unique subhuman primate model which allows sterile, repetitive access to cerebrospinal fluid, is utilized to study the CNS pharmacokinetics of various intrathecally and intravenously administered chemotherapeutic agents; to evaluate the neurotoxicities attendant upon various CNS treatments; and to evaluate and screen in a pre-clinical setting newer CNS treatment modalities and drug schedules. Information gained from the studies with this model is then applied to the design of clinical protocols used to treat patients with meningeal and non-meningeal malignancies. Current clinical studies of intrathecal AZQ and Concentration-x-Time intraventricular Ara-C are in progress. Pre-clinical studies evaluating intra-CSF drug administration via indwelling drug delivery devices is underway.